Many reports have been made on sustained-release microcapsules of various low-molecular water-soluble drugs e.g. JPA S57(1982)-118512, J. Pharm. Sci., 75, 750-755 (1986)!. Most of the microcapsules so far reported have the following drawbacks: (1) in the manufacturing process, the amount of the water-soluble drug leaked to the outer aqueous phase is relatively large to result in a relatively low entrapment ratio of the drug, and (2) the resulting microcapsules are generally porous and cause a relatively large initial drug release. Thus, at the present stage, sustained-release of water-soluble drugs over a sufficiently desirable long period have not yet been successfully prepared.
On the other hand, in recent years, novel peptides or low-molecular compounds having excellent cell-adhesion regulating or inhibiting actions have been found and are expected to be used as therapeutic agents of various diseases. For example, compounds having GPIIb/IIIa antagonistic activity remarkably inhibit platelet aggregation or suppress the metastasis of tumor cells and are expected to be clinically useful drugs. (Sci., 233, 467-469 (1986); Sci., 238, 1132-1134 (1987); Proc. Natl. Acad. Sci. USA, 87, 2471-2475(1990)!. As examples of such compounds, linear or cyclic peptides containing the amino acid sequence, -Arg-Gly-Asp-(RGD) have been known e.g. J. Biol. Chem., 262, 17294-17298 (1987); JPA H2(1990)-174797!. And, non-peptide compounds having an anti-thrombotic activity are disclosed in JPA H4(1992)-264068 and EPA No.505868, in which having 4- to 7-membered cyclic alkyleneimino such as a pyrrolidine ring and compounds having e.g. piperidine ring are respectively described. Further, compounds having piperidinone ring, which have cell-adhesion inhibiting activity, are disclosed in EPA No.529858.
These known compounds are not satisfactory from the viewpoint of the potency of their activity, undesirable side effects (e.g. prolonging bleeding time), absorbability, stability or durability of the action. Circumstances being such as above, there are problems still to be solved for clinical application of these compounds.
Recently, novel 2-piperazinone-1-acetic acid derivatives were synthesized and were found to possess, based on the chemical structural characteristic feature, a potent platelet aggregation inhibiting activity and, at the same time, are safely administrable, i.e. there are few undesirable side effects such as prolongation of bleeding time. These compounds are expected to be applied to a variety of circulatory diseases (e.g. thrombosis, transient cerebral ischemic attack, myocardial infarction, cerebral infarction, peripheral obstruction and arteriosclerotic obliteration), tumors, inflammatory diseases, or prevention of reobstruction and restenosis of coronary arteries after PTCA (percutaneous transluminal coronary angioplasty), prevention of reobstruction and restenosis after surgical operation for coronary artery bypass and secondary prophylaxis after re-opening of infarction. Especially, for patients of chronic diseases, administration of drugs for a long period is required. While preparations capable of sustained-release for a long period are desired, no report on sustained-release microcapsules of the above-mentioned novel compounds has been found.
Exploitation of a method of preparing sustained-release microcapsules which demonstrates a high entrapping ratio of a 2-piperazinone-1-acetic acid compound and a low initial release of the drug is expected.